DNA Repair and Genomic Instability in Cancer Development and Therapy

 描述（由申请人提供）：大多数（如果不是所有）肿瘤细胞都具有基因组不稳定性的迹象，这可能有助于其发展。DNA修复对抗基因组不稳定性，因此是一种强大的肿瘤抑制机制。编码修复因子的基因中的遗传突变与癌症易感性的显著增加相关，从而确定DNA损伤修复失败会导致或促进肿瘤的发展。尽管如此，DNA损伤疗法是最广泛使用和最成功的癌症疗法之一。癌细胞固有的基因组不稳定性使它们更容易受到高损伤负担的影响。这可以在临床上通过靶向对肿瘤细胞独特必需的特定DNA修复模块来利用。我们将建立一个蛋白质-蛋白质相互作用的地图，修复因子常见的多种修复途径。我们将确定蛋白质-蛋白质相互作用，这是特别增强或减少后处理与DNA拓扑异构酶抑制剂和DNA交联剂。这些差异调节模块将识别潜在的漏洞， 这将有助于癌细胞的DNA修复网络，并为精确的靶向治疗提供可能性。

 DESCRIPTION (provided by applicant): Most, if not all tumor cells harbor signs of genomic instability, which can contribute to their development. DNA repair combats genomic instability and thus, is a powerful tumor suppressor mechanism. Inherited mutations in genes encoding for repair factors are associated with significant increases in cancer susceptibility, establishing tha failure to repair DNA damage causes or facilitates tumor development. Nonetheless, DNA damaging therapies are amongst the most widely used and most successful cancer therapies. The inherent genomic instability of cancer cells makes them more vulnerable to a high damage burden. This can be exploited in the clinic by targeting specific DNA repair modules that are uniquely essential for tumor cells. We will build a map of protein-protein interactions for repair factors common to multiple repair pathways. We will identify protein-protein interactions, which are specifically enhanced or reduced following treatment with DNA topoisomerase inhibitors and DNA crosslinkers. These differentially regulated modules will identify potential vulnerabilities in the DNA repair networks of cancer cells and will open the possibility for precise, targeted therapies.